BK virus (BKV)-associated nephropathy (BKVN) is becoming increasingly appreciated as a significant factor in dysfunction and failure of renal transplants. By young adulthood, most individuals have been exposed to this uretheliotropic human polyomavirus, which establishes a persistent silent infection in the kidneys of immunocompetent individuals. Under conditions of immunosuppression (e.g., AIDS, BM transplantation, renal transplantation), however, high-level replication by BKV may ensue and result in a spectrum of severe urinary tract complications. Because Polyomaviridae are highly species-specific, we have begun exploring use of mouse polyomavirus in a murine renal transplant model to investigate the pathogenesis of polyomavirus-associated nephropathy in renal transplants and the potential protective and/or immunopathologic contributions of antiviral and anti-donor immune responses. In preliminary studies, we found that mouse polyomavirus replicates to >1000-fold higher levels in allogeneic than syngeneic kidney transplants in acutely infected mice, and is associated with accelerated allograft failure. We propose three, non-mutually exclusive, hypotheses to account for elevated polyomavirus replication in renal allografts: (1) failure of immune recognition of MHC-mismatched infected allograft cells; (2) alloreactive immune responses that alter the allograft microenvironment and produce a highly conducive state for viral replication; and (3) an inflammatory microenvironment secondary to active viral infection that triggers/accentuates alloreactivity. We have developed technologies to monitor mouse polyomavirus-specific and donor-specific CD8+ T cells in vivo at the single-cell level and to quantitate polyoma viral DNA. In this exploratory grant, we propose to use the polyomavirus-mouse renal transplant model (1) to refine and characterize a mouse model of polyomavirus-associated allograft nephropathy in the settings of acute and persistent viral infection and (2) to study the effect of varying degrees of MHC disparity on the pathogenesis of polyomavirus-associated allograft nephropathy. By combining the expertise of the laboratories of Drs. Larsen, Lukacher and Newell in this exploratory grant proposal, we have assembled a novel set of tools and resources to develop a greatly needed small animal model in which to study the pathogenesis of polyoma virus associated-allograft nephropathy.